The fibroblast growth factor (FGF) family consists of closely related polypeptide mitogens. This family includes at least seven members based on amino acid sequence homologies: basic FGF (Esch et al. (1985) Proc. Natl. Acad. Sci. USA 82:6507-6511; Abraham et al. (1986) Science 233:545-548; Abraham et al. (1986) EMBO J. 5:2523-2528; Kurokawa et al. (1987) FEBS Lett. 213:189-194), acidic FGF (Gimenez-Gallago et al. (1985) Science 230:1385-1388; Thomas et al. (1985) Proc. Natl. Acad. Sci. USA 82:6409-6413; Jaye et al. (1986) Science 233:543-545), int-2 (Moore et al. (1986) EMBO J. 5:919-924), hst (Kaposi sarcoma FGF) (Taira et al. (1987) Proc. Natl. Acad. Sci. USA 84:2980-2984; Bovi et al. (1987) Cell 50:729-737), FGF-5 (Zhan et al. (1988) Mol. Cell. Biol. 8:3487-3495), FGF-6 (Marics et al. (1989) Oncogene 4:335-340) and keratinocyte growth factor (KGF)(Finch et al. (1989) Science 245:752-755; Rubin et al. (1989) Proc. Natl. Acad. Sci. USA 86:802-806).
The pleiotropic effects of the FGF family members include proliferative activity for a wide variety of cells, neurotrophic activity and angiogenic activity (Gospodarowicz et al. (1986) Cell. Differ. 19:1-17; Morrison et al. (1986) Proc. Natl. Acad. Sci. USA 83:7537-7541; Walicke et al. (1986) Proc. Natl. Acad. Sci. USA 83:3012-3016; Folkman and Klagsbrun (1987) Science 235:442-447; Thomas (1987) FASEB J. 1:434-440; Anderson et al. (1988) Nature 332:360-361; Burgess and Maciag (1989) Annu. Rev. Biochem. 58:575-606). The FGFs also have the ability to influence the differentiation of a variety of cell types, exhibiting both differentiation-inducing and differentiation-inhibiting effects (Linkhart et al. (1981) Dev. Biol. 86:19-30; Serrero and Khoo (1982) Anal. Biochem. 120:351-359; Broad and Ham (1983) Eur. J. Biochem. 135:33-39; Lathrop et al. (1985) J. Cell. Biol. 100:1540-1547; Togari et al. (1985) J. Neurosci. 5:307-316; Wagner and D'Amore (1986) J. Cell. Biol. 103:1363-1367; Anderson et al. (1988) Nature 332:360-361). FGFs are also thought to play an important role in embryonal development (Kimelman and Kirschner (1987) Cell 51:869-877; Slack et al. (1987) Nature 326:197-200; Kimelman et al. (1988) Science 242:1053-1056; Amaya et al. (1991) Cell 66:257-270).
The FGFs mediate their effects by binding to high affinity cell surface receptors (reviewed in Johnson and Williams (1992) Adv. Cancer Res. 60:1-41). Four distinct FGF receptors have been identified: FGFR1 (also known was Flg, bFGFR, Cek1 or N-bFGFR) (Lee et al. (1989) Science 245:57-60; Dionne et al. (1990) EMBO J. 9:2685-2692; Johnson et al. (1990) Mol. Cell. Biol. 10:4728-4736; Eisemann et al. (1991) Oncogene 6:1195-1202; Hou et al. (1991) Science 251:665-668), FGFR2 (also known as Bek, Cek3, K-sam, TK14, TK25 or KGFR) (Dionne et al. (1990) EMBO J. 9:2685-2692; Hattori et al. (1990) Proc. Natl. Acad. Sci. USA 87:5983-5987; Miki et al. (1991) Science 251:72-75; Saiki et al. (1988) Science 239:487-491; Pasquale (1990) Proc. Natl. Acad. Sci. USA 87:5812-5816; Houssaint et al. (1990) Proc. Natl. Acad. Sci. USA 87:8180-8184; Champion-Arnaud et al. (1991) Oncogene 6:979-987; Crumley et al. (1991) Oncogene 6:2255-2262; Raz et al. (1991) Oncogene 6:753-760; Sato et al. (1991) Oncogene 6:1279-1283), FGFR3 (also known as Cek2) (Keegan et al. (1991) Proc. Natl. Acad. Sci. USA 88:1095-1099) and FGFR4 (Partanen et al. (1991) EMBO J. 10:1347-1354).
Structurally, the FGF receptors comprise an amino terminal signal peptide, three extracellular immunoglobulin-like domains (Ig domain I, Ig domain II, Ig domain III), with an acidic region between Ig domains I and II (the "acidic box" domain), a transmembrane region, and intracellular kinase domains (Johnson and Williams (1992) Adv. Cancer Res. 60:1-41). Variant forms of FGF receptors are generated by alternative mRNA splicing (Champion-Arnaud et al. (1991) Oncogene 6:979-987; Johnson et al. (1991) Mol. Cell. Biol. 11:4627-4634; Johnson and Williams (1992) Adv. Cancer Res. 60:1-41). Binding studies have demonstrated that multiple members of the FGF family can bind to the same receptor species (Dionne et al. (1990) EMBO J. 9:2685-2692; Johnson et al. (1990) Mol. Cell. Biol. 10:4728-4736; Mansukhani et al. (1990) Proc. Natl. Acad. Sci. USA 87:4378-4382; Keegan et al. (1991) Proc. Natl. Acad. Sci. USA 88:1095-1099). Alternative splice variants, particularly involving Ig domain III, are thought to be important in determining the ligand binding specificity of receptor species (Werner (1992) Mol. Cell. Biol. 12:82-88; Crumley et al. (1991) Oncogene 6:2255-2262). Moreover, analogous splice variants from different FGFR genes have been shown to encode receptor forms with different ligand binding specificities (Dionne et al. (1990) EMBO J. 9:2685-2692; Johnson et al. (1990) Mol. Cell. Biol. 10:4728-4736; Mansukhani et al. (1990) Proc. Natl. Acad. Sci. USA 87:4378-4382).
Given the role of FGF family members in a variety of biological processes, compounds that modulate FGF receptor activity would be advantageous. Certain retro-peptides have been described as FGF receptor blocking peptides (PCT Publication No. WO 92/13958). Moreover, soluble forms of FGF receptors, comprising the extracellular domains, have been described (U.S. Pat. No. 5,288,855 by Bergonzoni et al.; PCT Publication No. WO 91/00916; PCT Publication WO 92/00999; European Patent 529 076 B1). Additional compounds for modulating FGF receptor activity are still needed.